The goals of this project are to investigate the role of exposure to putative relapse triggers (such as stress and cues in the environment) in addiction and to develop and test treatments that prevent relapse. This project is largely translational, investigating whether the preclinical phenomenon of incubation of craving occurs in humans and whether pharmacological interventions identified in the preclinical reinstatement model are effective in humans. Summary Even for patients who have maintained long-term abstinence from drugs, relapse remains a substantial risk. As we have shown using ecological momentary assessment (EMA), lapses to drug use may follow acute increases in stress. In the rat reinstatement model of relapse, stress-induced seeking of heroin, cocaine, speedball (heroin-cocaine combination), alcohol, or nicotine is blocked by alpha-2 adrenoceptor agonists such as lofexidine, guanfacine, and clonidine. Thus, alpha-2 agonists may act on a final common pathway of stress-induced relapse, relevant to multiple drugs of abuse. In a randomized, placebo-controlled laboratory study, with non-treatment-seeking cocaine users, we have shown that clonidine was effective in reducing stress-induced (and, at a higher dose, cue-induced) craving in a pattern consistent with the findings from the reinstatement model. We have since shown, in a double-blind, randomized trial in abstinent opioid users receiving agonist maintenance, that adjuvant clonidine maintenance increase time to lapse and longest duration of abstinence. EMA data showed that heroin craving increased with increasing severity of stress; clonidine decoupled that association, and participants in the clonidine group reported less heroin craving. In contrast, clonidine did not alter craving responses to drug-cue exposure. Another medication that has been tested in the rat reinstatement model of relapse is aripiprazole, a D2 partial agonist used clinically to treat schizophrenia. In rats, aripiprazole blocks psychostimulant seeking induced by drug cues. To determine whether it would have this effect in humans, we enrolled cocaine-using methadone-maintained outpatients in a randomized clinical trial. To assist initial abstinence prior to randomization, participants earned vouchers for providing two weeks worth of thrice-weekly cocaine-negative urine specimens. Participants who achieved that criterion were randomized to receive aripiprazole (15/mg per day) or placebo for 25 weeks along with their daily methadone. The main outcome measure was latency to relapse, based on urine drug screens. We stopped the trial because too few (18 of 41) participants met the abstinence criterion. The results suggested that aripiprazole delayed lapse and relapse, but the effects did not reach statistical significance. Unexpectedly, the proportion of participants reporting cocaine craving was higher in the aripiprazole group, though frequency of craving was similar in the aripiprazole and placebo groups. These results did not support the utility of aripiprazole in recently abstinent cocaine users: it might delay relapse, but might also slightly increase craving. Difficulty in trial implementation underscores the fact that initial abstinence from cocaine is not a trivial hurdle. We also used EMA to investigate relationships among drinking, other drug use, and drug craving in a sample of 114 polydrug users who were not heavy drinkers and did not meet DSM criteria for alcohol abuse or dependence. Participants responded to 2-5 random prompts per day to report on their moods, cravings, and activities, and initiated entries when they used or acutely craved heroin or cocaine. Drinking alcohol was assessed in both types of entries. Breath alcohol was measured three times weekly. Participants reported drinking alcohol in 1.6% of random-prompt entries, 3.7% of event-contingent entries when craving cocaine and/or heroin, and 11.6% of event-contingent entries when using cocaine and/or heroin. Drinking was also associated with higher craving ratings, and with frequency of pre-study drinking. More drinking was detected by ambulatory self-report than by in-clinic breath testing. Even though we had screened out heavy drinkers from our sample of polydrug users, drinking was associated with heroin and cocaine craving and actual use. We are also evaluating the role of stress in relapse in a large natural-history study in which real-time field monitoring of stressor exposure is combined with continuous location tracking via GPS. Our preliminary analyses suggest some unexpected relationships between neighborhood environment and self-reported stress. As we collect more data, we should be able to determine how patterns of environmental-stressor exposure predict relapse. One of our goals is to supplement our ambulatory assessments with on-the-spot feedback, turning them into mobile interventions.